(1) Field of the Invention
The present invention relates to cytokine inhibitors. More specifically, the present invention identifies and characterizes several inhibitors of macrophage migration inhibitory factor.
(2) Description of the Related Art
Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine, critically involved in the pathogenesis of sepsis and other inflammatory disorders (Calandra and Roger, 2003; Riedemann et al., 2003). Sepsis, a lethal systemic inflammatory reaction to infection, kills more than 215,000 people per annum in the US alone. There is currently no anti-inflammatory therapeutic agent that is approved by the FDA, for its clinical management. MIF has been demonstrated to be an important late-acting mediator of systemic inflammation, and inhibiting its activity in vivo attenuates the lethal consequences of endotoxemia and sepsis in rodents (Calandra et al., 2000; Al-Abed et al., 2005).
MIF exists as a homotrimer (Sugimoto et al., 1995; Sun et al., 1996; Suzuki et al., 1996; Taylor et al., 1999) with the unique ability to catalyze the tautomerization of non-physiological substrates such as D-dopachrome and L-dopachrome methyl ester into their respective indole derivatives (Rosengren et al., 1996). While the physiological role of the tautomerase activity is uncertain, compounds that are structurally similar to D- and L-dopachrome can bind to and thereby block the MIF's tautomerase active site (Al-Abed et al., 2005; Cios et al., 2002; Cheng and Al-Abed, 2006; Lubetsky et al., 2002; Senter et al., 2002). N-acetyl-p-benzoquinone imine (NAPQI) forms a covalent complex with MIF at its active site (FIG. 1) and is capable of irreversibly inhibiting the adverse biological effect of MIF (Senter et al., 2002). However, the toxicity of NAPQI precludes its use as a viable clinical inhibitor of MIF.
Based on the above, the development of non-toxic small molecule inhibitors of MIF activity warrants further investigation.